Animal models are critical to understanding the biology of hematopoietic progenitor cells, HIV pathogenesis and pre-clinical evaluation of gene therapeutic strategies. The SCID-hu mouse, harboring a normally functioning human thymus, sustains thymopoiesis as long as one year and is shown to be susceptible to hematopoietic progenitor cells when transduced with retroviral vectors suitable for gene therapy and introduced into thymic grafts, develop into normal human T lymphocytes. Vector sequences were retained and expressed in these mature cells. Although the SCID-hu mouse system does not perfectly mimic all aspects of hematopoiesis and HIV pathogenesis, the combination of virus induced cell depletion and gene transduced CD34+ cell reconstitution taking place in a relatively short time provide us with an experimental system in which to address many critical issues relevant for the success of gene therapy approaches. Furthermore, at present the SCID-hu system is the only in vivo system to accurately evaluate the thymopoietic potential of vector transduced and HIV infected hematopoietic progenitor cells.